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  • Several effective strategies have been developed to design a

    2019-09-11

    Several effective strategies have been developed to design activatable MR probes according to the Solomon, Bloembergen and Morgan (SBM) theory, including modulation of the number of inner-sphere water molecules (q), the rotational tumbling time (τ) and the residence lifetime of inner-sphere water molecules (τm) 35., 38.. Modulation of the accessibility of hydration molecules (q) to the paramagnetic metal ion e.g., Gd3+) in the telomerase inhibitor agents has been demonstrated as an efficient approach, in which a “shielding” group is initially placed around the paramagnetic metal core and the subsequent removal of the “shielding” group by the target enzyme allows water molecules to coordinate with the paramagnetic ion, resulting in a significant increase in MR relaxivity [39]. Another type of activatable MRI probe involves receptor-induced magnetization enhancement (RIME), where the specific binding of contrast agents with the macromolecules of proteins (receptors or enzymes) prolongs the τR of the probe, leading to higher MR relaxivity 40., 41.. In addition, the alteration of MR contrast based on chemical exchange saturation transfer (CEST) has been demonstrated as a new class of activatable probe for MRI [42]. Weissleder and co-workers [43] reported an intriguing MR signal amplification strategy based on oxidoreductase-mediated polymerization of Gd monomers into oligomers with higher r1 relaxivity, which is amenable to the design of activatable probes for MR imaging of myeloperoxidase (MPO) activity in inflammation tissue. MPO has been recognized as an important biomarker of various inflammatory diseases, and accurate measurement of its activity is highly useful for both the early diagnosis of diseases and the monitoring of treatment efficacy. They designed the MPO-activatable MRI probes by conjugation of 5-hydroxytryptamide and Gd chelate (Fig. 3a). Upon interaction with MPO, these probes are catalyzed to form highly reactive radicals that can either proceed through rapid condensation into paramagnetic oligomers or react with other phenolic residues on the protein surface to form cross-linked structures with the proteins, resulting in a 70 %–100 % increase in r1 relaxivity due to a prolonged τR. MR imaging of MPO activity in vivo was first performed using an artificial Matrigel model implanted in mice, which showed striking differences both in MR contrast and pharmacokinetics between the MPO-implanted site and control site. They later applied the probes to in vivo MRI of lipopolysaccharide (LPS)-induced endogenous mouse MPO secretion in a myositis model, showing prolonged MR contrast enhancement relative to MPO-nonactivatable probes (Fig. 3b). Further application to in vivo imaging of MPO activity in the myocardium of mice was also demonstrated, which accurately detected MPO activity and had good sensitivity and dynamic range to monitor treatment effects [44]. Encouraged by this, the strategy of enzyme-mediated polymerization of Gd monomers into oligomers was extended by Liang and co-workers [45] to design an activatable MRI probe for highresolution visualization of furin levels in a human breast MDA-MB-468 tumor xenograft mouse model. Additionally, recent efforts have been made to develop new activatable MRI probes to detect other classes of enzymes, such as protein disulfide isomerase, which will allow for the detection of acute thrombosis [46].
    Activatable photoacoustic probes Photoacoustic (PA) imaging is a recently developed technique [47]. The imaging approach uses probes that absorb a pulsed laser beam and convert light energy into acoustic signals. It combines the advantages of the high sensitivity offered by optical imaging and the high spatial resolution offered by ultrasonic imaging. PA also enables high-throughput and real-time imaging and has wide applications for the in vivo molecular imaging of biological process 48., 49., 50., 51.. Currently, great attention has been paid to the development of activatable PA imaging probes for in vivo applications; however, only a few enzyme-activatable PA imaging probes have been reported due to the lack of an efficient approach to probe design. One of the first demonstrated concepts is based on enzyme-triggered in situ self-assembly to form nanomaterials, causing assembly-induced retention (AIR) to produce enhanced PA contrast at the target site [50]. The first enzyme-activated PA imaging probe was reported by Gambhir and co-workers [52] based on a biocompatible reaction-mediated probe self-assembly strategy. The probe showed a 7.1-fold PA signal in furin-positive MDA-MB-231 tumors than in furin-deficient LoVo tumors in mice. Encouraged by this result, Wang and co-workers [53] recently reported another work, wherein αvβ3 integrin-targeted probe delivery and the gelatinase-triggered formation of nanofibers significantly amplified the PA signal in a U87 tumor xenografted mouse model. Compound 1 was designed to include the NIR dye purpurin18 (P18) as a light absorber, a peptide sequence of PLGVRG as a selective substrate for gelatinase, and RGD as the targeting ligand (Fig. 4a). When the probe was injected into the vasculature, its small size and hydrophilic nature assisted in the diffusion, extravasation and targeting to the αvβ3 integrin that was overexpressed on the tumor cell membranes. The active gelatinase in the tumor microenvironment then cut the peptide to form hydrophobic P18-PLG molecules, which could self-assemble into nanofibers, exhibiting an AIR effect in tumors and resulting in an enhanced PA signal. A comparable study with compound 1, gelatinase-inert control compound 2 (P18-PMGMRGRGD) and compound 3 (P18-PLGVRGRDG), which is gelatinase sensitive but lacks the RGD moiety for targeting the αvß3 integrin, showed that the PA signal of a tumor treated with 1 was 16-fold that of 2 at 8h post-injection and nearly twofold that of 3 (Fig. 4b, c). These results indicated that both αvβ3 integrin-mediated probe delivery and gelatinase-triggered probe activation and retention contributed to the enhancement of the PA signal. In contrast to the activatable PA imaging probes based on the AIR effect, a new study using NIR-absorbing CuS nanoparticles and a red light-absorbing BHQ3 organic quencher to build an MMP-activatable PA imaging nanoprobe for ratiometric imaging of MMP activity in vivo was recently reported by Liu and co-authors [54]. This probe may represent an attractive strategy for the design of other enzyme-activatable PA imaging probes.